CHRONOPHARMACOLOGY OF GRANULOCYTE-COLONY-STIMULATING FACTOR IN MICE

The role of the sensitivity of bone marrow cells to, and the pharmacok inetics of granulocyte colony-stimulating factor (G-CSF) on the rhythm of leukocyte-increasing effect was investigated in ICR male mice hous ed under a standardized light-dark cycle (lights on at 0700, off at 19 00). A significant circadian rhythm was demonstrated for leukocyte cou nts at 24 hr after G-CSF (250 mu g/kg, s.c.) injection at six differen t circadian times (P <.01). The leukocyte counts of mice given G-CSF a t 0500, 0900, 1300 or 1700 were significantly higher than those of mic e given G-CSF at 2100 (P <.01, respectively). The rhythmic pattern res embled overall the rhythm occurring after saline injection. In the com parison between leukocyte counts after G-CSF injection at 0700 and 190 0, the time when leukocyte counts are equal in nondrugged state, the l eukocyte counts at 24 hr after G-CSF (250 mu g/kg, i.v.) injection wer e approximately 50% higher in mice injected with the drug at 0700 than at 1900 (P <.01). Bone marrow cultures obtained at two times of day r esulted in different numbers of myeloid colonies even when treated wit h the same concentrations of G-CSF in vitro. The colony-forming activi ty of G-CSF was significantly more potent at 0700 than at 1900 (P <.01 ). The plasma G-CSF concentrations after G-CSF (250 or 5 mu g/kg, i.v. ) injection were significantly higher in mice receiving injections wit h the drug at 0700 than at 1900 (P <.05, respectively). The area under the curve and mean residence time were significantly larger in mice i njected with the drug at 0700 than at 1900 (P <.01, P <.05, respective ly). Our suggests that the rhythm of G-CSF activity is caused by that of the sensitivity of bone marrow cells to, and the pharmacokinetics o f the drug.